Zohaib K Sherwani, Shari Damast, Emma C Fields, Sushil Beriwal, Zachary D Horne, Elizabeth A Kidd, Eric W Leung, Neil K Taunk, Junzo Chino, Andrea L Russo, Michael Dyer, Kevin V Albuquerque, Lara Hathout
{"title":"MLH1启动子高甲基化对辅助放疗治疗的I-II期子宫内膜癌预后的影响：一项多机构回顾性研究：MLH1在I-II期子宫内膜癌中的状态。","authors":"Zohaib K Sherwani, Shari Damast, Emma C Fields, Sushil Beriwal, Zachary D Horne, Elizabeth A Kidd, Eric W Leung, Neil K Taunk, Junzo Chino, Andrea L Russo, Michael Dyer, Kevin V Albuquerque, Lara Hathout","doi":"10.1016/j.ijrobp.2025.05.004","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>To assess the impact of MLH1 promoter hypermethylation (MLH1ph) on prognosis and define the patterns of recurrence in stage I-II endometroid endometrial cancer (EEC) treated with adjuvant radiotherapy.</p><p><strong>Materials and methods: </strong>In a retrospective, IRB-approved, multi-institutional cohort study, 814 patients with stage I-II EEC with known mismatch repair (MMR) status were included. Tumors with MSH2, MSH6, MLH1 or PMS2 mutations were classified as somatic dMMR (sdMMR), while tumors with epigenetic silencing of the MLH1 promoter were classified as MLH1ph. Recurrence-free survival (RFS) was calculated by the Kaplan Meier method. Univariate and multivariate analyses (UVA/MVA) were performed via Cox proportional hazards. Statistical analyses were conducted using SPSS version 27.</p><p><strong>Results: </strong>The median age at diagnosis was 65 (IQR 58-71) and most patients had grade 2-3 disease (59.2%), ≥50% myometrial invasion (56.0%) and absence of lymphovascular space invasion (58%). Vaginal brachytherapy was delivered to 643 (78.1%) patients, while 180 (21.9%) patients received external beam radiation (EBRT) ± VBT. MMR was proficient in 550 (67.6%) patients and deficient in 264 (32.4%) patients. Of the patients with dMMR, most patients harbored MLH1ph (n=171, 66%), while 93 patients (35.2%) had somatic dMMR. Tumor size ≥ 3.8cm (HR 2.2, p=0.003), MMR deficient vs proficient (HR 2.7, p<0.001) and EBRT±VBT vs VBT alone (HR 1.9, p=0.032) were associated with decreased RFS on MVA. On subgroup analysis including patients with dMMR only, patients with MLH1ph had worse RFS compared to patients with sdMMR (HR 1.9 (95% CI1.1-3.6), p=0.025). Distant recurrence was the most common recurrence site, regardless of MMR status. Patients with MLH1ph had significantly higher proportion of vaginal (5% vs 0% vs 2%) and pelvic (5.3% vs 3.2% vs 0.5%) recurrences compared with sdMMR and pMMR, respectively (p=0.038).</p><p><strong>Conclusion: </strong>Patients with MLH1ph had worse RFS, which may be attributed in part to a higher proportion of locoregional recurrences compared to the pMMR and sdMMR patients.</p>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":" ","pages":""},"PeriodicalIF":6.4000,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The prognostic impact of MLH1 promoter hypermethylation in stage I-II endometrial cancer treated with adjuvant radiotherapy: a multi-institutional retrospective study: MLH1ph status in stage I-II endometrial cancer.\",\"authors\":\"Zohaib K Sherwani, Shari Damast, Emma C Fields, Sushil Beriwal, Zachary D Horne, Elizabeth A Kidd, Eric W Leung, Neil K Taunk, Junzo Chino, Andrea L Russo, Michael Dyer, Kevin V Albuquerque, Lara Hathout\",\"doi\":\"10.1016/j.ijrobp.2025.05.004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>To assess the impact of MLH1 promoter hypermethylation (MLH1ph) on prognosis and define the patterns of recurrence in stage I-II endometroid endometrial cancer (EEC) treated with adjuvant radiotherapy.</p><p><strong>Materials and methods: </strong>In a retrospective, IRB-approved, multi-institutional cohort study, 814 patients with stage I-II EEC with known mismatch repair (MMR) status were included. Tumors with MSH2, MSH6, MLH1 or PMS2 mutations were classified as somatic dMMR (sdMMR), while tumors with epigenetic silencing of the MLH1 promoter were classified as MLH1ph. Recurrence-free survival (RFS) was calculated by the Kaplan Meier method. Univariate and multivariate analyses (UVA/MVA) were performed via Cox proportional hazards. Statistical analyses were conducted using SPSS version 27.</p><p><strong>Results: </strong>The median age at diagnosis was 65 (IQR 58-71) and most patients had grade 2-3 disease (59.2%), ≥50% myometrial invasion (56.0%) and absence of lymphovascular space invasion (58%). Vaginal brachytherapy was delivered to 643 (78.1%) patients, while 180 (21.9%) patients received external beam radiation (EBRT) ± VBT. MMR was proficient in 550 (67.6%) patients and deficient in 264 (32.4%) patients. Of the patients with dMMR, most patients harbored MLH1ph (n=171, 66%), while 93 patients (35.2%) had somatic dMMR. Tumor size ≥ 3.8cm (HR 2.2, p=0.003), MMR deficient vs proficient (HR 2.7, p<0.001) and EBRT±VBT vs VBT alone (HR 1.9, p=0.032) were associated with decreased RFS on MVA. On subgroup analysis including patients with dMMR only, patients with MLH1ph had worse RFS compared to patients with sdMMR (HR 1.9 (95% CI1.1-3.6), p=0.025). Distant recurrence was the most common recurrence site, regardless of MMR status. Patients with MLH1ph had significantly higher proportion of vaginal (5% vs 0% vs 2%) and pelvic (5.3% vs 3.2% vs 0.5%) recurrences compared with sdMMR and pMMR, respectively (p=0.038).</p><p><strong>Conclusion: </strong>Patients with MLH1ph had worse RFS, which may be attributed in part to a higher proportion of locoregional recurrences compared to the pMMR and sdMMR patients.</p>\",\"PeriodicalId\":14215,\"journal\":{\"name\":\"International Journal of Radiation Oncology Biology Physics\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":6.4000,\"publicationDate\":\"2025-05-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Radiation Oncology Biology Physics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ijrobp.2025.05.004\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Radiation Oncology Biology Physics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ijrobp.2025.05.004","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
The prognostic impact of MLH1 promoter hypermethylation in stage I-II endometrial cancer treated with adjuvant radiotherapy: a multi-institutional retrospective study: MLH1ph status in stage I-II endometrial cancer.
Purpose: To assess the impact of MLH1 promoter hypermethylation (MLH1ph) on prognosis and define the patterns of recurrence in stage I-II endometroid endometrial cancer (EEC) treated with adjuvant radiotherapy.
Materials and methods: In a retrospective, IRB-approved, multi-institutional cohort study, 814 patients with stage I-II EEC with known mismatch repair (MMR) status were included. Tumors with MSH2, MSH6, MLH1 or PMS2 mutations were classified as somatic dMMR (sdMMR), while tumors with epigenetic silencing of the MLH1 promoter were classified as MLH1ph. Recurrence-free survival (RFS) was calculated by the Kaplan Meier method. Univariate and multivariate analyses (UVA/MVA) were performed via Cox proportional hazards. Statistical analyses were conducted using SPSS version 27.
Results: The median age at diagnosis was 65 (IQR 58-71) and most patients had grade 2-3 disease (59.2%), ≥50% myometrial invasion (56.0%) and absence of lymphovascular space invasion (58%). Vaginal brachytherapy was delivered to 643 (78.1%) patients, while 180 (21.9%) patients received external beam radiation (EBRT) ± VBT. MMR was proficient in 550 (67.6%) patients and deficient in 264 (32.4%) patients. Of the patients with dMMR, most patients harbored MLH1ph (n=171, 66%), while 93 patients (35.2%) had somatic dMMR. Tumor size ≥ 3.8cm (HR 2.2, p=0.003), MMR deficient vs proficient (HR 2.7, p<0.001) and EBRT±VBT vs VBT alone (HR 1.9, p=0.032) were associated with decreased RFS on MVA. On subgroup analysis including patients with dMMR only, patients with MLH1ph had worse RFS compared to patients with sdMMR (HR 1.9 (95% CI1.1-3.6), p=0.025). Distant recurrence was the most common recurrence site, regardless of MMR status. Patients with MLH1ph had significantly higher proportion of vaginal (5% vs 0% vs 2%) and pelvic (5.3% vs 3.2% vs 0.5%) recurrences compared with sdMMR and pMMR, respectively (p=0.038).
Conclusion: Patients with MLH1ph had worse RFS, which may be attributed in part to a higher proportion of locoregional recurrences compared to the pMMR and sdMMR patients.
期刊介绍：
International Journal of Radiation Oncology • Biology • Physics (IJROBP), known in the field as the Red Journal, publishes original laboratory and clinical investigations related to radiation oncology, radiation biology, medical physics, and both education and health policy as it relates to the field.
This journal has a particular interest in original contributions of the following types: prospective clinical trials, outcomes research, and large database interrogation. In addition, it seeks reports of high-impact innovations in single or combined modality treatment, tumor sensitization, normal tissue protection (including both precision avoidance and pharmacologic means), brachytherapy, particle irradiation, and cancer imaging. Technical advances related to dosimetry and conformal radiation treatment planning are of interest, as are basic science studies investigating tumor physiology and the molecular biology underlying cancer and normal tissue radiation response.
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