{"paper_id":"f82befa0-5b81-44c5-8c4f-a6c4b7c1f092","body_text":"Exploring Nectin-4 as a Potential Prognostic Biomarker in Endometrial Adenocarcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Exploring Nectin-4 as a Potential Prognostic Biomarker in Endometrial Adenocarcinoma Melike Ordu, Serife Ozlem Genc This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7459698/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Dec, 2025 Read the published version in BMC Women's Health → Version 1 posted 18 You are reading this latest preprint version Abstract Background This study explored Nectin-4 expression in endometrial adenocarcinoma and examined its relationship with tumor grade, hormone receptor status, p53 expression, and mismatch repair (MMR) protein expression. Methods We retrospectively analyzed 55 paraffin-embedded tissue samples collected between 2015 and 2023, including endometrial adenocarcinoma, endometrial intraepithelial neoplasia (EIN), and normal endometrium samples. Nectin-4 expression was assessed via immunohistochemistry, and correlations with clinicopathological features and molecular markers were evaluated statistically. Results Nectin-4 expression increased with histological grade (p < 0.001). All Grade III tumors presented strong expression, whereas lower-grade tumors presented variable staining. The expression of these genes was also correlated with p53 overexpression (p = 0.007) and PMS2 loss (p = 0.002). Nectin-4 was absent in normal tissues and weakly expressed in EIN. Conclusion Nectin-4 expression is linked to high-grade endometrial carcinoma and abnormal p53 expression, supporting its potential role as a prognostic biomarker. Larger studies are needed to validate its clinical use. Nectin-4 Endometrial adenocarcinoma Immunohistochemistry Mismatch repair proteins p53 Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Endometrial adenocarcinoma is the most common gynecological cancer in developed countries and remains a major health burden worldwide [ 1 ]. Endometrial cancers are traditionally divided into two groups. Type I tumors, which are mainly endometrioid adenocarcinomas, make up approximately 80% of cases. They are often estrogen-dependent and associated with favorable outcomes, MSI, or PTEN mutations [ 2 ]. Type II tumors, such as serous carcinomas, are less common but more aggressive and typically harbor p53 mutations and chromosomal instability [ 3 ]. Molecular classifications have refined risk assessment. The Cancer Genome Atlas (TCGA) describes four subtypes: POLE ultramutated, MSI-high, p53-abnormal (copy number high), and p53-wild type (copy number low), each with different prognostic implications [ 4 ]. The ProMisE classifier translates these into clinically useful categories, focusing on MMR deficiency, POLE mutations, and p53 abnormalities [ 5 ]. Nevertheless, variability within groups highlights the need for additional biomarkers [ 6 ]. Cell adhesion molecules have recently been investigated for their role in invasion, metastasis, and immune escape [ 7 ]. Nectin-4, a member of this family, is overexpressed in several cancers, including breast, ovarian, pancreatic, and urothelial tumors [ 8 , 9 ]. Its presence is correlated with advanced disease, aggressiveness, and poor survival, highlighting its value as both a biomarker and a therapeutic target [ 10 , 11 ]. In gynecologic cancers, Nectin-4 has been linked to higher grade, abnormal p53 expression, and MMR deficiency [ 12 , 13 ]. Because it is a cell surface protein, it is also a promising target for therapies such as enfortumab vedotin, an antibody–drug conjugate already in clinical use for bladder cancer [ 14 ]. Thus, we investigated Nectin-4 expression in endometrial adenocarcinoma and its relationship with tumor grade, p53 status, and MMR proteins. Methods We analyzed 55 paraffin-embedded tissue samples collected between 2015 and 2023. The cases included 35 endometrioid endometrial adenocarcinomas (17 grade 1, 10 grade 2, and 8 grade 3), 10 EIN cases, and 10 normal endometrium samples. All histological diagnoses and grades were confirmed by a pathologist. Sections (4 µm) were stained with primary anti-Nectin-4 antibody (clone ab192033, Abcam, 1:200) via an automated system (VENTANA Discovery XT, Ventana Medical Systems, Tucson, AZ). OptiView DAB IHC v4 software and an OptiView DAB IHC Detection Kit with amplification were used. Antigen retrieval was performed with Cell Conditioning Solution 2 (CC2, Ventana) for 32 minutes. A universal linker and horseradish peroxidase (HRP) multimer were applied for 8 minutes each, followed by an OptiView Amplifier and amplification multimer for 4 minutes each. Hematoxylin was used for counterstaining. Urothelial carcinoma tissue served as a positive control. The same detection system was also used for MPO and LCA staining on the BenchMark ULTRA platform. A blinded pathologist scored the intensity and percentage of positive tumor cells. The H score was calculated as follows: H score = Σ (staining intensity × percentage of positive cells). Staining was graded as 0 (negative), 1+ (weak), 2+ (moderate), or 3+ (strong). Molecular Markers: p53: wild-type (scattered) or mutant-like (overexpressed/absent). MMR proteins (MLH1, PMS2, MSH2, MSH6): MMR deficiency was defined as the loss of nuclear staining for any protein. ER and PR: positive if ≥ 1% nuclear staining was detected. Analyses were conducted with SPSS version 26.0 (IBM Corp., Armonk, NY, USA). Chi-square tests and Fisher’s exact tests were used for categorical variables. Kruskal‒Wallis and Mann‒Whitney U tests were used for continuous variables. Spearman’s correlation: relationships among Nectin-4, grade, and p53. p < 0.05 was considered significant. Since no prior study reported power estimates for Nectin-4 in endometrial adenocarcinoma, we conducted a post hoc analysis. According to the observed association between Nectin-4 and histological grade, Cohen’s w was 0.75 (large effect). With α = 0.05, 20 cases yield 90% power. Our dataset of 55 cases provided > 95% power, confirming adequate study strength. Results We analyzed 55 cases: 35 carcinomas, 10 EINs, and 10 normal endometria. The median age overall was 56 years; in carcinoma cases, it was 63 years. Representative immunohistochemical images show weak (Fig. 1 ), moderate (Fig. 2 ), and strong (Fig. 3 ) Nectin-4 expression in endometrioid endometrial carcinoma. Nectin-4 was strongly expressed in Grade 3 tumors (87.5%). Grade 1 and 2 tumors presented weaker expression (p = 0.002). No expression was detected in normal tissues or in EIN. Representative images demonstrate intact nuclear staining of MMR proteins (Fig. 4 ) and complete loss of nuclear expression (Fig. 5 ). Tumors with wild-type p53 had lower Nectin-4 expression. All p53-overexpressing cells were strongly positive for Nectin-4 (p = 0.007) (Table 1 ). PMS2 loss was strongly associated with high Nectin-4 expression (64.3%, p = 0.002) (Table 1 ). No significant associations were found with MLH1, MSH2, or MSH6 (p > 0.05). PMS2 expression also varied significantly with histological grade (p = 0.002) (Table 1 ). Table 1 Correlation of Nectin-4 Expression with p53, MMR Proteins, and Hormone Receptors Nectin-4 No Expression Mild Expression Moderate Expression Severe Expression p p53 Wild 0 (0) 10 (33.33) 12 (40) 8 (26.67) 0.007* p53 Overexpression 0 (0) 0 (0) 0 (0) 5 (100) MLH1 No loss 0 (0) 10 (31.25) 11 (34.38) 11 (34.38) 0.762 MLH1 Loss 0 (0) 0 (0) 1 (33.33) 2 (66.67) PMS2 No loss 0 (0) 10 (47.62) 7 (33.33) 4 (19.05) 0.002* PMS2 Loss 0 (0) 0 (0) 5 (35.71) 9 (64.29) MSH2 No loss 0 (0) 10 (29.41) 11 (32.35) 13 (38.24) 0.629 MSH2 Loss 0 (0) 0 (0) 1 (100) 0 (0) MSH6 No loss 0 (0) 10 (38.46) 8 (30.77) 8 (30.77) 0.065 MSH6 Loss 0 (0) 0 (0) 4 (44.44) 5 (55.56) Age - Mean ± SD 40.12 ± 6.20 54.85 ± 5.68 68.42 ± 8.93 63.46 ± 5.21 < 0.001** Survival - Mean ± SD - 4.20 ± 1.03 3.83 ± 1.27 3.08 ± 0.95 0.059 Nectin-4 expression increased with age (p < 0.001, r = 0.62). Survival was lower in patients with high Nectin-4 levels, but the difference was not statistically significant (p = 0.059). Discussion Endometrial cancers are heterogeneous, with variations in molecular and clinical behavior [ 1 , 4 , 5 ]. Current classifications, including TCGA and ProMisE, have improved risk stratification but still leave gaps [ 4 – 6 ]. Our study provides evidence that Nectin-4 expression, which is absent in the normal endometrium and EIN, increases sharply in high-grade tumors, supporting its role as a marker of aggressiveness [ 9 , 10 ]. High Nectin-4 has been linked to poor survival in patients with breast, urothelial, pancreatic, and ovarian cancers [ 11 – 15 ]. Meta-analyses confirm its broad prognostic value [ 10 , 16 ]. As a surface protein, it is also an attractive therapeutic target [ 14 , 17 ]. TP53 mutations are frequent in high-grade endometrial carcinoma [ 18 – 20 ]. These tumors behave aggressively and respond poorly to therapy [ 20 ]. Our data revealed that all p53-abnormal tumors also strongly expressed Nectin-4, suggesting an interaction between adhesion molecules and the p53 pathway [ 21 ]. This aligns with findings in ovarian and bladder cancers [ 22 , 23 ]. Such tumors may represent a particularly aggressive subgroup. MMR deficiency drives MSI, a hallmark of Lynch syndrome [ 4 , 12 ]. Approximately 20–30% of sporadic tumors are MSI-high, mostly due to MLH1 promoter hypermethylation [ 24 ]. Since MLH1 and PMS2 form a heterodimer, MLH1 loss usually results in PMS2 loss. Isolated PMS2 loss is rare and often linked to Lynch syndrome. The predominance of PMS2 loss in our cohort may reflect unique biology or hereditary risk. We found that PMS2 loss was correlated with high Nectin-4 expression, supporting reports that Nectin-4 is enriched in MMR-deficient cancers [ 12 ]. These findings suggest that Nectin-4 may contribute to immune evasion in MSI-high tumors [ 25 ]. IHC for MSI is already widely used [ 26 ], and adding Nectin-4 could refine risk assessment. As isolated PMS2 loss also signals Lynch syndrome [ 27 ], the integration of Nectin-4 may provide insights into hereditary risk and therapeutic vulnerabilities. Nectin-4 is already targeted in bladder cancer patients with enfortumab vedotin [ 28 ]. Our findings support the use of similar strategies in endometrial carcinoma. Combination with immunotherapy may be especially effective in MMR-deficient tumors [ 30 ]. Emerging evidence suggests that Nectin-4 positivity could predict the response to ADC therapy [ 31 ]. Ongoing studies are exploring mechanisms of resistance, such as ABC transporters [ 32 ]. This retrospective, single-institution study has a modest sample size and limited follow-up. Nevertheless, these findings highlight the potential prognostic and therapeutic role of Nectin-4. Future prospective studies should explore the mechanisms linking the Nectin-4, p53, and MMR pathways [ 34 ]. Trials of Nectin-4–directed therapies in gynecologic cancers are warranted [ 28 – 32 ], and such approaches may also contribute to broader innovations in gynecological cancer management [ 33 ]. Conclusion Nectin-4 expression increases with tumor grade and is correlated with p53 overexpression and PMS2 loss in endometrial adenocarcinoma. It shows promise as a prognostic marker and potential therapeutic target. Larger, multicenter studies are needed to confirm these findings and explore Nectin-4–directed strategies in high-risk patients. Abbreviations ADC Antibody–Drug Conjugate CC2 Cell Conditioning Solution 2 DNA Deoxyribonucleic Acid EIN Endometrial Intraepithelial Neoplasia ER Estrogen Receptor FFPE Formalin-Fixed, Paraffin-Embedded FIGO International Federation of Gynecology and Obstetrics HRP Horseradish Peroxidase IHC Immunohistochemistry MMR Mismatch Repair MSI Microsatellite Instability MSH2 / MSH6 MutS Homolog 2 / 6 MLH1 MutL Homolog 1 PMS2 Postmeiotic Segregation Increased 2 POLE DNA Polymerase Epsilon PR Progesterone Receptor ProMisE Proactive Molecular Risk Classifier for Endometrial Cancer SPSS Statistical Package for the Social Sciences TCGA The Cancer Genome Atlas TP53 Tumor Protein p53 Declarations Ethics Approval and Consent to Participate The Aksaray University Clinical Research Ethics Committee approved this study (Decision No: 2022/18 − 04). The study followed the Declaration of Helsinki. Written informed consent was obtained from all participants. Consent for publication Not applicable. Funding None. Author Contribution SOG conceived and designed the study, interpreted the data, and drafted the manuscript. MO contributed to data collection, evaluation, and statistical analysis. Both authors reviewed and revised the manuscript critically for important intellectual content. All authors approved the submitted version of the manuscript and agree to be accountable for their own contributions as well as for ensuring the accuracy and integrity of the work. Acknowledgement Not applicable. Data Availability The datasets generated and analyzed during the current study are not publicly available due to institutional restrictions and patient confidentiality, but are available from the corresponding author on reasonable request. References Brüggmann D, Ouassou K, Klingelhöfer D, Bohlmann MK, Jaque J, Groneberg DA. Endometrial cancer: mapping the global landscape of research. J Transl Med. 2020;18:386. 10.1186/s12967-020-02554-y . Yi M, Li T, Niu M, Luo S, Chu Q, Wu K. 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19:00:50\",\"extension\":\"html\",\"order_by\":16,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":95057,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"earlyproof.html\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7459698/v1/4d664e5cad00a09edb27121e.html\"},{\"id\":92207040,\"identity\":\"e40b9895-7934-45af-82fa-2fb2b2ba13a3\",\"added_by\":\"auto\",\"created_at\":\"2025-09-25 19:00:50\",\"extension\":\"jpeg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":54276,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eWeak cytoplasmic expression of Nectin-4 in endometrioid endometrial carcinoma (Immunohistochemical staining, original magnification ×10).\\u003c/strong\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage1.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7459698/v1/8136e94fe0765d4b7c6e1ee4.jpeg\"},{\"id\":92207601,\"identity\":\"c769db95-32cd-47c5-87b2-6489a290246c\",\"added_by\":\"auto\",\"created_at\":\"2025-09-25 19:08:50\",\"extension\":\"jpeg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":78483,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eModerate cytoplasmic expression of Nectin-4 in endometrioid endometrial carcinoma (immunohistochemical staining, original magnification ×10).\\u003c/strong\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage2.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7459698/v1/a92e2ece3b1100f67ae9844d.jpeg\"},{\"id\":92207039,\"identity\":\"6d97e353-2e6f-4528-bf3a-f0e039fbaca6\",\"added_by\":\"auto\",\"created_at\":\"2025-09-25 19:00:50\",\"extension\":\"jpeg\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":87758,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eStrong cytoplasmic and membranous expression of Nectin-4 in endometrioid endometrial carcinoma (immunohistochemical staining, original magnification ×10).\\u003c/strong\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage3.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7459698/v1/91325cc3cef62a666e961626.jpeg\"},{\"id\":92207050,\"identity\":\"f949d1a2-15df-4e86-b2e7-a2414177e59b\",\"added_by\":\"auto\",\"created_at\":\"2025-09-25 19:00:50\",\"extension\":\"jpeg\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":1373788,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eNo loss of nuclear expression of mismatch repair (MMR) proteins in endometrioid endometrial carcinoma (immunohistochemical staining, original magnification ×20)\\u003c/strong\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage4.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7459698/v1/6466c1c85706c3697e3eb7dc.jpeg\"},{\"id\":92207924,\"identity\":\"ca975448-7073-4edb-b12e-f0d6cc2f7dc1\",\"added_by\":\"auto\",\"created_at\":\"2025-09-25 19:16:50\",\"extension\":\"jpeg\",\"order_by\":5,\"title\":\"Figure 5\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":1073123,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eLoss of nuclear expression of MMR proteins (immunohistochemical staining, original magnification ×20). The positive internal control was tumor-infiltrating lymphocytes with preserved nuclear staining.\\u003c/strong\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage6.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7459698/v1/6c37e9082e9fdffbdc292526.jpeg\"},{\"id\":98814281,\"identity\":\"b4606f4d-04c5-4e67-8aaf-d2cadf39554f\",\"added_by\":\"auto\",\"created_at\":\"2025-12-22 16:12:13\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":3498316,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7459698/v1/7fa311ba-93d3-4d35-a5df-4d94aaf1f121.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Exploring Nectin-4 as a Potential Prognostic Biomarker in Endometrial Adenocarcinoma\",\"fulltext\":[{\"header\":\"Background\",\"content\":\"\\u003cp\\u003eEndometrial adenocarcinoma is the most common gynecological cancer in developed countries and remains a major health burden worldwide [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. Endometrial cancers are traditionally divided into two groups. Type I tumors, which are mainly endometrioid adenocarcinomas, make up approximately 80% of cases. They are often estrogen-dependent and associated with favorable outcomes, MSI, or PTEN mutations [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. Type II tumors, such as serous carcinomas, are less common but more aggressive and typically harbor p53 mutations and chromosomal instability [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eMolecular classifications have refined risk assessment. The Cancer Genome Atlas (TCGA) describes four subtypes: POLE ultramutated, MSI-high, p53-abnormal (copy number high), and p53-wild type (copy number low), each with different prognostic implications [\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. The ProMisE classifier translates these into clinically useful categories, focusing on MMR deficiency, POLE mutations, and p53 abnormalities [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]. Nevertheless, variability within groups highlights the need for additional biomarkers [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eCell adhesion molecules have recently been investigated for their role in invasion, metastasis, and immune escape [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]. Nectin-4, a member of this family, is overexpressed in several cancers, including breast, ovarian, pancreatic, and urothelial tumors [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]. Its presence is correlated with advanced disease, aggressiveness, and poor survival, highlighting its value as both a biomarker and a therapeutic target [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eIn gynecologic cancers, Nectin-4 has been linked to higher grade, abnormal p53 expression, and MMR deficiency [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]. Because it is a cell surface protein, it is also a promising target for therapies such as enfortumab vedotin, an antibody\\u0026ndash;drug conjugate already in clinical use for bladder cancer [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eThus, we investigated Nectin-4 expression in endometrial adenocarcinoma and its relationship with tumor grade, p53 status, and MMR proteins.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cp\\u003eWe analyzed 55 paraffin-embedded tissue samples collected between 2015 and 2023. The cases included 35 endometrioid endometrial adenocarcinomas (17 grade 1, 10 grade 2, and 8 grade 3), 10 EIN cases, and 10 normal endometrium samples. All histological diagnoses and grades were confirmed by a pathologist.\\u003c/p\\u003e\\u003cp\\u003eSections (4 \\u0026micro;m) were stained with primary anti-Nectin-4 antibody (clone ab192033, Abcam, 1:200) via an automated system (VENTANA Discovery XT, Ventana Medical Systems, Tucson, AZ). OptiView DAB IHC v4 software and an OptiView DAB IHC Detection Kit with amplification were used. Antigen retrieval was performed with Cell Conditioning Solution 2 (CC2, Ventana) for 32 minutes. A universal linker and horseradish peroxidase (HRP) multimer were applied for 8 minutes each, followed by an OptiView Amplifier and amplification multimer for 4 minutes each. Hematoxylin was used for counterstaining. Urothelial carcinoma tissue served as a positive control. The same detection system was also used for MPO and LCA staining on the BenchMark ULTRA platform.\\u003c/p\\u003e\\u003cp\\u003eA blinded pathologist scored the intensity and percentage of positive tumor cells. The H score was calculated as follows:\\u003c/p\\u003e\\u003cp\\u003eH score\\u0026thinsp;=\\u0026thinsp;Σ (staining intensity \\u0026times; percentage of positive cells).\\u003c/p\\u003e\\u003cp\\u003eStaining was graded as 0 (negative), 1+ (weak), 2+ (moderate), or 3+ (strong).\\u003c/p\\u003e\\u003cp\\u003eMolecular Markers:\\u003c/p\\u003e\\u003cp\\u003e\\u003cul\\u003e\\u003cli\\u003e\\u003cp\\u003ep53: wild-type (scattered) or mutant-like (overexpressed/absent).\\u003c/p\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cp\\u003eMMR proteins (MLH1, PMS2, MSH2, MSH6): MMR deficiency was defined as the loss of nuclear staining for any protein.\\u003c/p\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cp\\u003eER and PR: positive if\\u0026thinsp;\\u0026ge;\\u0026thinsp;1% nuclear staining was detected.\\u003c/p\\u003e\\u003c/li\\u003e\\u003c/ul\\u003e\\u003c/p\\u003e\\u003cp\\u003eAnalyses were conducted with SPSS version 26.0 (IBM Corp., Armonk, NY, USA).\\u003c/p\\u003e\\u003cp\\u003e\\u003cul\\u003e\\u003cli\\u003e\\u003cp\\u003eChi-square tests and Fisher\\u0026rsquo;s exact tests were used for categorical variables.\\u003c/p\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cp\\u003eKruskal‒Wallis and Mann‒Whitney U tests were used for continuous variables.\\u003c/p\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cp\\u003eSpearman\\u0026rsquo;s correlation: relationships among Nectin-4, grade, and p53.\\u003c/p\\u003e\\u003c/li\\u003e\\u003c/ul\\u003e\\u003c/p\\u003e\\u003cp\\u003ep\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05 was considered significant.\\u003c/p\\u003e\\u003cp\\u003eSince no prior study reported power estimates for Nectin-4 in endometrial adenocarcinoma, we conducted a post hoc analysis. According to the observed association between Nectin-4 and histological grade, Cohen\\u0026rsquo;s w was 0.75 (large effect). With α\\u0026thinsp;=\\u0026thinsp;0.05, 20 cases yield 90% power. Our dataset of 55 cases provided \\u0026gt;\\u0026thinsp;95% power, confirming adequate study strength.\\u003c/p\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003eWe analyzed 55 cases: 35 carcinomas, 10 EINs, and 10 normal endometria. The median age overall was 56 years; in carcinoma cases, it was 63 years.\\u003c/p\\u003e\\u003cp\\u003eRepresentative immunohistochemical images show weak (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e), moderate (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e), and strong (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e) Nectin-4 expression in endometrioid endometrial carcinoma. Nectin-4 was strongly expressed in Grade 3 tumors (87.5%). Grade 1 and 2 tumors presented weaker expression (p\\u0026thinsp;=\\u0026thinsp;0.002). No expression was detected in normal tissues or in EIN.\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003eRepresentative images demonstrate intact nuclear staining of MMR proteins (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e) and complete loss of nuclear expression (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig5\\\" class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003e). Tumors with wild-type p53 had lower Nectin-4 expression. All p53-overexpressing cells were strongly positive for Nectin-4 (p\\u0026thinsp;=\\u0026thinsp;0.007) (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003ePMS2 loss was strongly associated with high Nectin-4 expression (64.3%, p\\u0026thinsp;=\\u0026thinsp;0.002) (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). No significant associations were found with MLH1, MSH2, or MSH6 (p\\u0026thinsp;\\u0026gt;\\u0026thinsp;0.05). PMS2 expression also varied significantly with histological grade (p\\u0026thinsp;=\\u0026thinsp;0.002) (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eCorrelation of Nectin-4 Expression with p53, MMR Proteins, and Hormone Receptors\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"6\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eNectin-4\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eNo\\u003c/p\\u003e\\u003cp\\u003eExpression\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eMild\\u003c/p\\u003e\\u003cp\\u003eExpression\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eModerate\\u003c/p\\u003e\\u003cp\\u003eExpression\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eSevere\\u003c/p\\u003e\\u003cp\\u003eExpression\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ep\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003ep53 Wild\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e10 (33.33)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e12 (40)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e8 (26.67)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.007*\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003ep53 Overexpression\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e5 (100)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eMLH1 No loss\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e10 (31.25)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e11 (34.38)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e11 (34.38)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.762\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eMLH1 Loss\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e1 (33.33)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e2 (66.67)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003ePMS2 No loss\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e10 (47.62)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e7 (33.33)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e4 (19.05)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.002*\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003ePMS2 Loss\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e5 (35.71)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e9 (64.29)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eMSH2 No loss\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e10 (29.41)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e11 (32.35)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e13 (38.24)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.629\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eMSH2 Loss\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e1 (100)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eMSH6 No loss\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e10 (38.46)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e8 (30.77)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e8 (30.77)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.065\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eMSH6 Loss\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e4 (44.44)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e5 (55.56)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eAge - Mean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e40.12\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;6.20\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e54.85\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;5.68\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e68.42\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;8.93\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e63.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;5.21\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001**\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eSurvival - Mean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e4.20\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.03\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e3.83\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.27\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e3.08\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.95\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.059\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003eNectin-4 expression increased with age (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001, r\\u0026thinsp;=\\u0026thinsp;0.62). Survival was lower in patients with high Nectin-4 levels, but the difference was not statistically significant (p\\u0026thinsp;=\\u0026thinsp;0.059).\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eEndometrial cancers are heterogeneous, with variations in molecular and clinical behavior [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]. Current classifications, including TCGA and ProMisE, have improved risk stratification but still leave gaps [\\u003cspan additionalcitationids=\\\"CR5\\\" citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]. Our study provides evidence that Nectin-4 expression, which is absent in the normal endometrium and EIN, increases sharply in high-grade tumors, supporting its role as a marker of aggressiveness [\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eHigh Nectin-4 has been linked to poor survival in patients with breast, urothelial, pancreatic, and ovarian cancers [\\u003cspan additionalcitationids=\\\"CR12 CR13 CR14\\\" citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]. Meta-analyses confirm its broad prognostic value [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]. As a surface protein, it is also an attractive therapeutic target [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eTP53 mutations are frequent in high-grade endometrial carcinoma [\\u003cspan additionalcitationids=\\\"CR19\\\" citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]. These tumors behave aggressively and respond poorly to therapy [\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]. Our data revealed that all p53-abnormal tumors also strongly expressed Nectin-4, suggesting an interaction between adhesion molecules and the p53 pathway [\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e]. This aligns with findings in ovarian and bladder cancers [\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]. Such tumors may represent a particularly aggressive subgroup.\\u003c/p\\u003e\\u003cp\\u003eMMR deficiency drives MSI, a hallmark of Lynch syndrome [\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]. Approximately 20\\u0026ndash;30% of sporadic tumors are MSI-high, mostly due to MLH1 promoter hypermethylation [\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]. Since MLH1 and PMS2 form a heterodimer, MLH1 loss usually results in PMS2 loss. Isolated PMS2 loss is rare and often linked to Lynch syndrome. The predominance of PMS2 loss in our cohort may reflect unique biology or hereditary risk.\\u003c/p\\u003e\\u003cp\\u003eWe found that PMS2 loss was correlated with high Nectin-4 expression, supporting reports that Nectin-4 is enriched in MMR-deficient cancers [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]. These findings suggest that Nectin-4 may contribute to immune evasion in MSI-high tumors [\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e]. IHC for MSI is already widely used [\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e], and adding Nectin-4 could refine risk assessment. As isolated PMS2 loss also signals Lynch syndrome [\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e], the integration of Nectin-4 may provide insights into hereditary risk and therapeutic vulnerabilities.\\u003c/p\\u003e\\u003cp\\u003eNectin-4 is already targeted in bladder cancer patients with enfortumab vedotin [\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e]. Our findings support the use of similar strategies in endometrial carcinoma. Combination with immunotherapy may be especially effective in MMR-deficient tumors [\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e]. Emerging evidence suggests that Nectin-4 positivity could predict the response to ADC therapy [\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e]. Ongoing studies are exploring mechanisms of resistance, such as ABC transporters [\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eThis retrospective, single-institution study has a modest sample size and limited follow-up. Nevertheless, these findings highlight the potential prognostic and therapeutic role of Nectin-4. Future prospective studies should explore the mechanisms linking the Nectin-4, p53, and MMR pathways [\\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e]. Trials of Nectin-4\\u0026ndash;directed therapies in gynecologic cancers are warranted [\\u003cspan additionalcitationids=\\\"CR29 CR30 CR31\\\" citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e], and such approaches may also contribute to broader innovations in gynecological cancer management [\\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e].\\u003c/p\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eNectin-4 expression increases with tumor grade and is correlated with p53 overexpression and PMS2 loss in endometrial adenocarcinoma. It shows promise as a prognostic marker and potential therapeutic target. Larger, multicenter studies are needed to confirm these findings and explore Nectin-4\\u0026ndash;directed strategies in high-risk patients.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cdiv class=\\\"DefinitionList\\\"\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eADC\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eAntibody\\u0026ndash;Drug Conjugate\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eCC2\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eCell Conditioning Solution 2\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eDNA\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eDeoxyribonucleic Acid\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eEIN\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eEndometrial Intraepithelial Neoplasia\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eER\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eEstrogen Receptor\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eFFPE\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eFormalin-Fixed, Paraffin-Embedded\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eFIGO\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eInternational Federation of Gynecology and Obstetrics\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eHRP\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eHorseradish Peroxidase\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eIHC\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eImmunohistochemistry\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eMMR\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eMismatch Repair\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eMSI\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eMicrosatellite Instability\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eMSH2 / MSH6\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eMutS Homolog 2 / 6\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eMLH1\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eMutL Homolog 1\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003ePMS2\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003ePostmeiotic Segregation Increased 2\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003ePOLE\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eDNA Polymerase Epsilon\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003ePR\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eProgesterone Receptor\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eProMisE\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eProactive Molecular Risk Classifier for Endometrial Cancer\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eSPSS\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eStatistical Package for the Social Sciences\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eTCGA\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eThe Cancer Genome Atlas\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003e\\u003cb\\u003eTP53\\u003c/b\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eTumor Protein p53\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eEthics Approval and Consent to Participate\\u003c/strong\\u003e\\u003cp\\u003eThe Aksaray University Clinical Research Ethics Committee approved this study (Decision No: 2022/18\\u0026thinsp;\\u0026minus;\\u0026thinsp;04). The study followed the Declaration of Helsinki. Written informed consent was obtained from all participants.\\u003c/p\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication\\u003c/strong\\u003e\\u003cp\\u003eNot applicable.\\u003c/p\\u003e\\u003c/p\\u003e\\u003ch2\\u003eFunding\\u003c/h2\\u003e\\u003cp\\u003eNone.\\u003c/p\\u003e\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003eSOG conceived and designed the study, interpreted the data, and drafted the manuscript. MO contributed to data collection, evaluation, and statistical analysis. Both authors reviewed and revised the manuscript critically for important intellectual content. All authors approved the submitted version of the manuscript and agree to be accountable for their own contributions as well as for ensuring the accuracy and integrity of the work.\\u003c/p\\u003e\\u003ch2\\u003eAcknowledgement\\u003c/h2\\u003e\\u003cp\\u003eNot applicable.\\u003c/p\\u003e\\u003ch2\\u003eData Availability\\u003c/h2\\u003e\\u003cp\\u003eThe datasets generated and analyzed during the current study are not publicly available due to institutional restrictions and patient confidentiality, but are available from the corresponding author on reasonable request.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eBr\\u0026uuml;ggmann D, Ouassou K, Klingelh\\u0026ouml;fer D, Bohlmann MK, Jaque J, Groneberg DA. Endometrial cancer: mapping the global landscape of research. 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Front Immunol. 2025;16:1571800. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.3389/fimmu.2025.1571800\\u003c/span\\u003e\\u003cspan address=\\\"10.3389/fimmu.2025.1571800\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-womens-health\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bmwh\",\"sideBox\":\"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/bmwh/default.aspx\",\"title\":\"BMC Women's Health\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Nectin-4, Endometrial adenocarcinoma, Immunohistochemistry, Mismatch repair proteins, p53\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7459698/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7459698/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e\\u003cp\\u003eThis study explored Nectin-4 expression in endometrial adenocarcinoma and examined its relationship with tumor grade, hormone receptor status, p53 expression, and mismatch repair (MMR) protein expression.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e\\u003cp\\u003eWe retrospectively analyzed 55 paraffin-embedded tissue samples collected between 2015 and 2023, including endometrial adenocarcinoma, endometrial intraepithelial neoplasia (EIN), and normal endometrium samples. Nectin-4 expression was assessed via immunohistochemistry, and correlations with clinicopathological features and molecular markers were evaluated statistically.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e\\u003cp\\u003eNectin-4 expression increased with histological grade (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001). All Grade III tumors presented strong expression, whereas lower-grade tumors presented variable staining. The expression of these genes was also correlated with p53 overexpression (p\\u0026thinsp;=\\u0026thinsp;0.007) and PMS2 loss (p\\u0026thinsp;=\\u0026thinsp;0.002). Nectin-4 was absent in normal tissues and weakly expressed in EIN.\\u003c/p\\u003e\\u003ch2\\u003eConclusion\\u003c/h2\\u003e\\u003cp\\u003eNectin-4 expression is linked to high-grade endometrial carcinoma and abnormal p53 expression, supporting its potential role as a prognostic biomarker. Larger studies are needed to validate its clinical use.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Exploring Nectin-4 as a Potential Prognostic Biomarker in Endometrial Adenocarcinoma\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-09-25 19:00:45\",\"doi\":\"10.21203/rs.3.rs-7459698/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2025-10-16T18:25:24+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-10-16T13:02:43+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-10-13T19:37:13+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-10-09T14:00:42+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-10-09T09:41:56+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"293582819038677080645246496329174762526\",\"date\":\"2025-10-09T03:26:26+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"225377235194994172010978711274281118009\",\"date\":\"2025-10-09T02:00:10+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"9726544394198155279987270189548816559\",\"date\":\"2025-10-08T01:10:15+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"305203466534428200825798743512262410390\",\"date\":\"2025-10-07T13:10:54+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-10-02T13:00:47+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"82062902865193732343465961122256496649\",\"date\":\"2025-10-02T10:42:00+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"146381304809546192037059605349954709158\",\"date\":\"2025-09-29T14:04:07+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"79853269336471083320151769802562935890\",\"date\":\"2025-09-29T10:19:21+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2025-09-16T11:10:37+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvited\",\"content\":\"\",\"date\":\"2025-08-28T17:46:53+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2025-08-28T00:11:21+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2025-08-28T00:11:09+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"BMC Women's Health\",\"date\":\"2025-08-26T06:54:57+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-womens-health\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bmwh\",\"sideBox\":\"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/bmwh/default.aspx\",\"title\":\"BMC Women's Health\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"b46103f1-b532-4eb8-a792-3a5fe0e5ba33\",\"owner\":[],\"postedDate\":\"September 25th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-12-22T16:08:12+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-7459698\",\"link\":\"https://doi.org/10.1186/s12905-025-04227-8\",\"journal\":{\"identity\":\"bmc-womens-health\",\"isVorOnly\":false,\"title\":\"BMC Women's Health\"},\"publishedOn\":\"2025-12-19 15:57:48\",\"publishedOnDateReadable\":\"December 19th, 2025\"},\"versionCreatedAt\":\"2025-09-25 19:00:45\",\"video\":\"\",\"vorDoi\":\"10.1186/s12905-025-04227-8\",\"vorDoiUrl\":\"https://doi.org/10.1186/s12905-025-04227-8\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7459698\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7459698\",\"identity\":\"rs-7459698\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC0","license_restricted":false}